NSUN6, short for Nop2/Sun RNA methyltransferase family member 6, is an RNA 5-methylcytosine (m5C) methyltransferase. It targets mRNA, mainly at the three prime untranslated regions (3'UTR) with a consensus sequence motif CTCCA in hairpin loop structures. This methylation can influence mRNA and translation levels, potentially acting as a quality-control mechanism in translation termination [2].

In cervical cancer, NSUN6 overexpression promotes radioresistance by enhancing the m5C modification of NDRG1 mRNA, which stabilizes NDRG1 mRNA via ALYREF binding and leads to homologous recombination-mediated DNA repair [1]. In colon adenocarcinoma, high NSUN6 expression is associated with shorter survival, and it promotes cell cycle progression and cell proliferation by upregulating METTL3 and catalyzing its m5C modification [4]. In lung cancer, NSUN6 restricts cell proliferation, migration, and epithelial-mesenchymal transition (EMT) by regulating NM23-H1 expression through m5C modification of its 3'-UTR [5]. In osteosarcoma, NSUN6 is upregulated, and its loss reduces cell proliferation, migration, and invasion by downregulating EEF1A2 expression and inhibiting Akt/mTOR signaling pathway activation in an m5C-dependent manner [6]. Also, biallelic pathogenic variants in NSUN6 cause autosomal recessive intellectual disability, as demonstrated by affected individuals with developmental and behavioral anomalies and Drosophila with locomotion and learning impairment upon NSUN6 ortholog ablation [3].

In summary, NSUN6 is a crucial m5C methyltransferase. Its functions are revealed through various in vivo and functional studies across different disease models. It significantly impacts cancer-related processes such as radioresistance, tumor cell proliferation, and metastasis, as well as neurodevelopmental processes, highlighting its potential as a biomarker and therapeutic target in these disease areas.

References:

1. Yu, Min, Ni, Mengdong, Xu, Fei, Li, Jiajia, Ke, Guihao. 2024. NSUN6-mediated 5-methylcytosine modification of NDRG1 mRNA promotes radioresistance in cervical cancer. In Molecular cancer, 23, 139. doi:10.1186/s12943-024-02055-2. https://pubmed.ncbi.nlm.nih.gov/38970106/

2. Selmi, Tommaso, Hussain, Shobbir, Dietmann, Sabine, Bornelöv, Susanne, Frye, Michaela. . Sequence- and structure-specific cytosine-5 mRNA methylation by NSUN6. In Nucleic acids research, 49, 1006-1022. doi:10.1093/nar/gkaa1193. https://pubmed.ncbi.nlm.nih.gov/33330931/

3. Mattioli, Francesca, Worpenberg, Lina, Li, Cai-Tao, Roignant, Jean-Yves, Reymond, Alexandre. 2023. Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder. In Genetics in medicine : official journal of the American College of Medical Genetics, 25, 100900. doi:10.1016/j.gim.2023.100900. https://pubmed.ncbi.nlm.nih.gov/37226891/

4. Cui, Yuanbo, Lv, Pengju, Zhang, Chunyan. . NSUN6 mediates 5-methylcytosine modification of METTL3 and promotes colon adenocarcinoma progression. In Journal of biochemical and molecular toxicology, 38, e23749. doi:10.1002/jbt.23749. https://pubmed.ncbi.nlm.nih.gov/38800929/

5. Lu, Zhansheng, Liu, Bo, Kong, Demiao, Pei, Dengke, Liu, Di. 2023. NSUN6 Regulates NM23-H1 Expression in an m5C Manner to Affect Epithelial-Mesenchymal Transition in Lung Cancer. In Medical principles and practice : international journal of the Kuwait University, Health Science Centre, 33, 56-65. doi:10.1159/000535479. https://pubmed.ncbi.nlm.nih.gov/38029727/

6. Hu, Sang, Yang, Min, Xiao, Kangwen, Wang, Linlong, Wei, Renxiong. 2023. Loss of NSUN6 inhibits osteosarcoma progression by downregulating EEF1A2 expression and activation of Akt/mTOR signaling pathway via m5C methylation. In Experimental and therapeutic medicine, 26, 457. doi:10.3892/etm.2023.12156. https://pubmed.ncbi.nlm.nih.gov/37614424/